Individual prediction of long-term outcome in adolescents at ultra-high risk for psychosis: Applying machine learning techniques to brain imaging data.

An important focus of studies of individuals at ultra-high risk (UHR) for psychosis has been to identify biomarkers to predict which individuals will transition to psychosis. However, the majority of individuals will prove to be resilient and go on to experience remission of their symptoms and function well. The aim of this study was to investigate the possibility of using structural MRI measures collected in UHR adolescents at baseline to quantitatively predict their long-term clinical outcome and level of functioning. We included 64 UHR individuals and 62 typically developing adolescents (12-18 years old at recruitment). At six-year follow-up, we determined resilience for 43 UHR individuals. Support Vector Regression analyses were performed to predict long-term functional and clinical outcome from baseline MRI measures on a continuous scale, instead of the more typical binary classification. This led to predictive correlations of baseline MR measures with level of functioning, and negative and disorganization symptoms. The highest correlation (r = 0.42) was found between baseline subcortical volumes and long-term level of functioning. In conclusion, our results show that structural MRI data can be used to quantitatively predict long-term functional and clinical outcome in UHR individuals with medium effect size, suggesting that there may be scope for predicting outcome at the individual level. Moreover, we recommend classifying individual outcome on a continuous scale, enabling the assessment of different functional and clinical scales separately without the need to set a threshold. Hum Brain Mapp 38:704-714, 2017. © 2016 Wiley Periodicals, Inc.

The importance of informal support and a listening ear: A narrative analysis of emotional conflict and support needs of siblings of children with a psychiatric disorder.

This study investigates the self-reported impact of children's psychiatric disorders on their siblings and assesses what forms of support such children most value. We used a qualitative research design with open interviews to stimulate children between 8 and 15 years old to talk about their experiences living with a brother or sister with a psychiatric disorder. Their stories were analysed within a hermeneutic phenomenological framework in order to identify narrative themes and interpret the meaning of shared experiences. From our analysis, nine shared narrative themes emerge. Overall, siblings report feeling conflicted about adapting their lives to their brother's or sister's disorder and signal a need for personalized attention from parents. They also indicate that being involved in the care for their brother or sister helps them to better understand their behaviour. Finally, siblings reveal that, in their experience, formal, protocolized forms of support foreground family problems and stress. Thus, we recommend to involve children in the care process; to acknowledge their personal needs and conflicts; and to be mindful of the style of support: help offered in an informal or playful way, instead of formal and protocolized, could be a more effective way of meeting siblings' needs.

Reduced prepulse inhibition in adolescents at risk for psychosis: a 2-year follow-up study.

BACKGROUND: Reduced prepulse inhibition (PPI) of the auditory startle reflex is a hallmark feature of attention-processing deficits in patients with schizophrenia and other psychotic disorders. Recent evidence suggests that these deficits may also be present before the onset of psychosis in individuals at ultra-high risk (UHR) and become progressively worse as psychosis develops. We conducted a longitudinal follow-up study to observe the development of PPI over time in UHR adolescents and healthy controls. METHODS: Two-year follow-up data of PPI measures were compared between UHR adolescents and a matched control group of typically developing individuals. RESULTS: We included 42 UHR adolescents and 32 matched controls in our study. Compared with controls, UHR individuals showed reduced PPI at both assessments. Clinical improvement in UHR individuals was associated with an increase in PPI parameters. LIMITATIONS: A developmental increase in startle magnitude partially confined the interpretation of the association between clinical status and PPI. Furthermore, post hoc analyses for UHR individuals who became psychotic between assessments had limited power owing to a low transition rate (14%). CONCLUSION: Deficits in PPI are present before the onset of psychosis and represent a stable vulnerability marker over time in UHR individuals. The magnitude of this marker may partially depend on the severity of clinical symptoms.

Affective dysfunctions in adolescents at risk for psychosis: emotion awareness and social functioning.

Studies of individuals at ultra high risk (UHR) for psychosis have revealed deviations in cognitive and neural development before the onset of psychosis. As affective impairments are among the core dysfunctions in psychotic disorders such as schizophrenia, this study assessed emotion processing and the relationship with social competence in adolescents at risk for psychosis. Thirty-four adolescents at UHR for psychosis and twenty-three non-clinical controls completed the Bermond-Vorst Alexithymia Questionnaire, a measure of emotion awareness. Social inadequacy was measured using the Dutch Personality Questionnaire. Schizophrenia spectrum psychopathology was assessed using self-report and clinical instruments. The Wechsler Adult Intelligence Scale (WAIS) was used to evaluate intellectual functioning. UHR adolescents showed difficulties in identifying and verbalizing their own emotions, independent of intelligence scores. Emotion awareness problems were related to social inadequacy and schizotypal traits in the high risk group. These findings suggest that UHR adolescents may have reduced emotion awareness, independent of intellectual functioning. The relationship with social inadequate behavior fits with the idea that emotion awareness is a prerequisite for the regulation of emotions in social contexts. In the search for early vulnerability markers of risk for psychosis, studying emotion processing besides cognitive abilities might increase our understanding of 'at risk' developmental pathways.

Brain development in adolescents at ultra-high risk for psychosis: Longitudinal changes related to resilience.

BACKGROUND: The main focus of studies of individuals at ultra-high risk for psychosis (UHR) has been on identifying brain changes in those individuals who will develop psychosis. However, longitudinal studies have shown that up to half of UHR individuals are resilient, with symptomatic remission and good functioning at follow-up. Yet little is known about brain development in resilient individuals. Therefore, the aim of this study was to investigate differences in brain development between resilient and non-resilient individuals. METHODS: A six-year longitudinal structural MRI study was performed with up to three scans per individual. The final sample consisted of 48 UHR individuals and 48 typically developing controls with a total of 225 MRI-scans, aged 12-20 years at the time of the first MRI-scan and matched for age, gender and number of follow-up scans. At six-year follow-up, 35 UHR individuals were divided in resilient (good functional outcome) and non-resilient (poor functional outcome) subgroups, defined by the modified Global Assessment of Functioning. The main outcome measures were developmental changes in MR-based measures of cortical and subcortical anatomy. RESULTS: We found widespread differences in volume of frontal, temporal and parietal cortex between resilient and non-resilient individuals. These were already present at baseline and remained stable over development (12-24 years). Furthermore, there were differences in the development of cortical surface area in frontal regions including cingulate gyrus. CONCLUSIONS: Developmental differences may reflect compensatory neural mechanisms, where better functioning in resilient individuals leads to less tissue loss over development.

Brain volume changes in first-episode schizophrenia: a 1-year follow-up study.

BACKGROUND: Imaging studies of patients with schizophrenia have demonstrated that brain abnormalities are largely confined to decreases in gray matter volume and enlargement of the lateral and third ventricles. Global gray matter volume has been reported to progressively decrease in childhood-onset and chronic schizophrenia. Global gray matter volumes have not been examined longitudinally in patients with first-episode schizophrenia. One would expect global gray matter to decrease progressively, particularly in first-episode patients, because clinical deterioration is greatest in the early stages of the disease. METHODS: Patients with first-episode schizophrenia who had taken antipsychotic medication for 0 to 16 weeks (n = 34) and matched healthy comparison subjects (n = 36) were included in the study. For all subjects, magnetic resonance imaging scans of the whole brain were obtained at inclusion and after 1 year (mean [SD], 12.7 [1.1] months). Outcome was measured 2 years after inclusion. To compare morphological changes over time between patients and healthy comparison subjects, multiple repeated-measures analyses of variance were conducted with intracranial volume as a covariate. Outcome and cumulative antipsychotic medication were related to changes in patients' brain volumes. RESULTS: Total brain volume (-1.2%) and gray matter volume of the cerebrum (-2.9%) significantly decreased and lateral ventricle volume significantly increased (7.7%) in patients. The decrease in global gray matter volume significantly correlated with outcome and, independently of that, with higher cumulative dosage of antipsychotic medication. CONCLUSIONS: The loss of global gray matter in schizophrenia is progressive, occurs at an early stage of the illness, and is related to the disease process and antipsychotic medication.

Childhood trauma and clinical outcome in patients at ultra-high risk of transition to psychosis.

BACKGROUND: Although transition rates in 'ultra-high risk' (UHR) for psychosis samples are declining, many young individuals at UHR still experience attenuated positive symptoms and impaired functioning at follow-up. The present study examined the association between a history of childhood trauma and transition to psychosis, and symptomatic and functional outcome, in UHR patients. METHOD: Data on childhood trauma were available for 125 UHR individuals. Cox regression and linear regression analyses were used to determine the association between childhood trauma, and clinical and functional outcome, during the 24-month follow-up. RESULTS: Of the 125 UHR subjects 26 individuals (20.8%) transitioned to psychosis within 24 months. Childhood trauma did not predict transition to psychosis. However, at 24-month follow-up, UHR patients with higher levels of childhood trauma had higher levels of attenuated positive symptoms (b = 0.34, t = 2.925, p < 0.01), general symptoms (b = 0.29, t = 2.707, p < 0.01) and depression (b = 0.32, t = 2.929, p < 0.01) and lower levels of global functioning (b = − 0.33, t = − 2.853, p = 0.01). Childhood trauma was not significantly associated with a differential course of symptoms over time, although in those with higher levels of childhood trauma, attenuated positive symptoms were more persistent at a trend level. CONCLUSIONS: Our results suggest that childhood trauma may contribute to a shared vulnerability for several psychopathological domains.

Neurocognitive and clinical predictors of long-term outcome in adolescents at ultra-high risk for psychosis: a 6-year follow-up.

BACKGROUND: Most studies aiming to predict transition to psychosis for individuals at ultra-high risk (UHR) have focused on either neurocognitive or clinical variables and have made little effort to combine the two. Furthermore, most have focused on a dichotomous measure of transition to psychosis rather than a continuous measure of functional outcome. We aimed to investigate the relative value of neurocognitive and clinical variables for predicting both transition to psychosis and functional outcome. METHODS: Forty-three UHR individuals and 47 controls completed an extensive clinical and neurocognitive assessment at baseline and participated in long-term follow-up approximately six years later. UHR adolescents who had converted to psychosis (UHR-P; n = 10) were compared to individuals who had not (UHR-NP; n = 33) and controls on clinical and neurocognitive variables. Regression analyses were performed to determine which baseline measures best predicted transition to psychosis and long-term functional outcome for UHR individuals. RESULTS: Low IQ was the single neurocognitive parameter that discriminated UHR-P individuals from UHR-NP individuals and controls. The severity of attenuated positive symptoms was the only significant predictor of a transition to psychosis and disorganized symptoms were highly predictive of functional outcome. CONCLUSIONS: Clinical measures are currently the most important vulnerability markers for long-term outcome in adolescents at imminent risk of psychosis.

Quantitative and qualitative symptomatic differences in individuals at Ultra-High Risk for psychosis and healthy controls.

Patients at Ultra-High Risk (UHR) for developing a first psychosis vary widely in their symptom presentation and illness course. An important aim in UHR research concerns the characterization of the clinical heterogeneity in this population. We aimed to identify qualitatively and quantitatively different clinical symptom profiles at baseline and at 2-year follow-up in a group of UHR subjects and healthy controls. We employed a Latent Class Factor Analysis (LCFA) to the 19 items of the Structured Interview for Prodromal Syndromes (SIPS) ratings at baseline and at 2-year follow-up in a sample of 147 UHR subjects and 141 controls from the Dutch Prediction of Psychosis Study (DUPS) in the Netherlands. Additionally, a stepwise logistic regression analysis was performed with transition to psychosis as a dependent variable and baseline latent variable scores as predictors. Variation in symptomatology at baseline was explained by both quantitative and qualitative differences; at 2-year follow-up qualitative differences between individuals were no longer observed. Quantitative differences showed moderate stability over time (range=0.109-0.42). Within the UHR sample, transition to psychosis was significantly associated with quantitative differences in baseline SIPS scores. The results of our study suggest a 'quasi'-continuous extended psychosis phenotype, a finding that merits replication in other samples.

Progressive structural brain changes during development of psychosis.

BACKGROUND: Ultra-high risk (UHR) for psychosis has been associated with widespread structural brain changes in young adults. The onset of these changes and their subsequent progression over time are not well understood. METHODS: Rate of brain change over time was investigated in 43 adolescents at UHR for psychosis compared with 30 healthy controls. Brain volumes (total brain, gray matter, white matter [WM], cerebellum, and ventricles), cortical thickness, and voxel-based morphometry were measured at baseline and at follow-up (2 y after baseline) and compared between UHR individuals and controls. Post hoc analyses were done for UHR individuals who became psychotic (N = 8) and those who did not (N = 35). RESULTS: UHR individuals showed a smaller increase in cerebral WM over time than controls and more cortical thinning in the left middle temporal gyrus. Post hoc, a more pronounced decrease over time in total brain and WM volume was found for UHR individuals who became psychotic relative to controls and a greater decrease in total brain volume than individuals who were not psychotic. Furthermore, UHR individuals with subsequent psychosis displayed more thinning than controls in widespread areas in the left anterior cingulate, precuneus, and temporo-parieto-occipital area. Volume loss in the individuals who developed psychosis could not be attributed to medication use. CONCLUSION: The development of psychosis during adolescence is associated with progressive structural brain changes around the time of onset. These changes cannot be attributed to (antipsychotic) medication use and are therefore likely to reflect a pathophysiological process related to clinical manifestation of psychosis.

Reduced prepulse inhibition as an early vulnerability marker of the psychosis prodrome in adolescence.

BACKGROUND: The onset of psychosis is thought to be preceded by neurodevelopmental changes in the brain. However, the timing and nature of these changes have not been established. The aim of the present study was to determine whether three "classic" neurophysiological markers of schizophrenia are also characteristic of young adolescents (12-18 years) at ultra-high risk for psychosis (UHR). METHODS: 63 young UHR individuals and 68 typically developing, age-, sex- and IQ-matched controls were recruited for neurophysiological assessment. Data for P50 suppression, prepulse inhibition (PPI) and smooth pursuit eye movements (SPEM) were gathered and compared. RESULTS: UHR individuals showed reduced PPI compared to controls, which became more pronounced when controls were directly compared to medication-naive UHR individuals (N=39). There were no group differences in P50 or SPEM measures. CONCLUSIONS: These results suggest that PPI is a relatively early vulnerability marker, while changes in other neurophysiological measures may only be detected or affected later during the illness course. Antipsychotic and antidepressant medication may aid in elevating PPI levels and potentially have a neuroprotective effect.

Transition and remission in adolescents at ultra-high risk for psychosis.

BACKGROUND: Future success of early intervention initiatives to prevent the onset of psychosis will rely on the validity of methods to predict clinical outcome. Proper identification is particularly essential for young adolescents, as psychotic-like symptoms are often transitory during this period and mislabeling can lead to early stigmatization and unnecessary treatment. This article presents results from a prospective, naturalistic 2-year follow-up study of a cohort of young adolescents putatively at ultra-high risk (UHR) for psychosis. METHODS: Seventy-two adolescents between 12 and 18years were recruited, fulfilling either UHR criteria or the basic symptom-based criterion cognitive disturbances (COGDIS). Incidence of transition as well as the remission rate from UHR status was calculated. Individuals who made a transition (UHR-P) were compared to those who did not (UHR-NP) and to those who remitted (UHR-R) on socio-demographic and clinical characteristics. RESULTS: Fifty-seven UHR individuals completed the 2-year follow-up assessment. The confirmed transition rate was 15.6% and 35.3% still met UHR criteria. The remaining 49.1% had remitted from an initial UHR status. The UHR subgroups did not differ on socio-demographic or clinical variables at baseline. CONCLUSIONS: Half of young adolescents meeting UHR criteria continue to experience prodromal or psychotic symptoms after 2 years. However, they are at least three times more likely to have remitted from their UHR status than to have made a transition to psychosis. In addition, baseline characteristics are not indicative of clinical outcome at follow-up. Our results emphasize the need for further improvement and stratification of relative risk factors for psychosis.

The genetic overlap of attention deficit hyperactivity disorder and autistic spectrum disorder.

Autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are classified as distinct disorders within the DSM-IV-TR (1994). The manual excludes simultaneous use of both diagnoses in case of overlap on a symptomatic level. However this does not always represent clinical observations and findings of previous studies. This review explores the genetic basis of the phenomenological overlap between ADHD and ASD. Based on an extensive review of twin-, linkage-, association studies, and reported structural genomic abnormalities associated with these disorders, we have identified seventeen regions on the human genome that can be related to both disorders. These regions of shared genetic association are: 2q35, 3p14, 4p16.1, 4p16.3, 5p15.31, 5p15.33, 7p12.3, 7p22, 7q21, 8q24.3, 14q12, 15q11-12, 16p13, 17q11, 18q21-23, 22q11.2, Xp22.3. The presented data are of interest for future genetic studies and appear to suggest the existence of a phenotype partition that may differ from the current classification of psychiatric disorders.

Psychopharmacology for children: from off label use to registration.

Pharmacological treatment of children and adolescents is largely based on evidence from adults' studies. There is, however, growing awareness that this evidence cannot simply be extrapolated to children. The Dutch Medicines Evaluation Board (MEB) in collaboration with the Child and Adolescent section of the Dutch Association of Psychiatry and the National Expertise Centre Child and Adolescent Psychiatry have organised a workshop to discuss the kind of evidence that would be necessary and the methods involved. There was consensus about the need to demonstrate efficacy in targeted disorders as well as symptoms within specific disorders and about the need for separate evidence for children and for adolescents. In addition, too little is known about safety, especially long-term safety, as consequences of treatment. Main issues are effects on growth, cognitive, motor, emotional, and sexual development, metabolic symptoms, cardiotoxicity, and dependence. Specific methodological issues were discussed, such as the role of different informants and the high rate of comorbidity.

No evidence for structural brain changes in young adolescents at ultra high risk for psychosis.

OBJECTIVE: The onset of psychosis is thought to be preceded by neurodevelopmental changes in the brain. However, the timing of these changes has not been established. We investigated structural brain changes in a sample of young adolescents (12-18 years) at ultra high-risk for psychosis (UHR). METHODS: Structural MRI data from young UHR subjects (n=54) and typically developing, matched controls (n=54) were acquired with a 1.5 Tesla scanner and compared. RESULTS: None of the measures differed between UHR subjects and controls. CONCLUSIONS: Our results do not support the presence of gross neuroanatomical changes in young UHR subjects. This suggests that early changes are too subtle to detect with conventional imaging techniques. Therefore, changes observed in older cohorts may only onset later developmentally or occur secondary to prodromal symptoms.

Theory of mind in schizophrenia: meta-analysis.

BACKGROUND: Mentalising impairment (an impaired ability to think about people in terms of their mental states) has frequently been associated with schizophrenia. AIMS: To assess the magnitude of the deficit and analyse associated factors. METHOD: Twenty-nine studies of mentalising in schizophrenia (combined n=1518), published between January 1993 and May 2006, were included to estimate overall effect size. Study descriptors predicted to influence effect size were analysed using weighted regression-analysis techniques. Separate analyses were performed for symptom subgroups and task types. RESULTS: The estimated overall effect size was large and statistically significant (d=-1.255, P<0.0001) and was not significantly affected by sample characteristics. All symptom subgroups showed significant mentalising impairment, but participants with symptoms of disorganisation were significantly more impaired than the other subgroups (P<0.01). CONCLUSIONS: This meta-analysis showed significant and stable mentalising impairment in schizophrenia. The finding that patients in remission are also impaired favours the notion that mentalising impairment represents a possible trait marker of schizophrenia.

Characteristics of early psychosis.

There is little research on characteristics related to course and prognosis of early-onset psychosis. The present article aims to advance our knowledge of this disorder for the purpose of proper diagnosis and treatment. It focuses on premorbid and prodromal characteristics, treatment history, symptoms and classifications, and differences between subgroups with affective and schizophrenic psychosis. A chart review was constructed to study a group of 129 subjects (12-18 years) with psychotic symptoms referred to the University Medical Center in Utrecht. The group was characterized by early-but nonspecific-treatment, developmental problems (mostly social), and clear prodromal symptoms. Drug abuse, depressive symptoms, and suicidal behavior were also frequent. Male sex, a relatively long prodromal phase, school problems, and drug abuse were more indicative of the schizophrenic subgroup. Introversion was characteristic for boys with schizophrenia. Classifications, however, were not stable. These findings suggest that early recognition of psychosis can be enhanced in health and youth care facilities. Careful examination of the prodromal phase seems helpful to differentiate between schizophrenic and affective psychosis.